Tissue factor (TF) is a 47 kDa transmembrane glycoprotein. Under normal physiological conditions, TF expression is mainly restricted to the cells in subendothelial layer; once the blood vessels are damaged in an organism, TF will be exposed to the blood stream, and initiates extrinsic coagulation reaction by binding to and activating factor VII.
It has been found in studies that TF is abnormally activated and expressed in many tumor tissues, and plays an important role in the development and progression of tumors. Especially in the advanced stage of cancer, most patients are accompanied by spontaneous thrombosis, such as Deep-vein thrombosis (DVT), Disseminated intravascular coagulation (DIC) and Pulmonary embolism (PE) (Thrombosis research, 2013, 131: S59-S62; Journal of Thrombosis and Haemostasis, 2011, 9(s1): 306-315); the abnormal expression of TF in tumor cells is the main cause responsible for these symptoms. Analysis on clinical samples of many tumors shows that the expression level of TF directly affects the deterioration indexes such as metastasis of tumor and occurrence of thrombosis in patients, for example, the percentage of abnormal TF expression was 85.8% in breast cancer, 88.5% in pancreatic cancer, 83.6% in lung cancer, and 91.3% in esophageal cancer, etc. (Blood, 2012, 119: 924-932).
In addition to the initiation of the extrinsic coagulation reaction, a TF/FVIIa complex can directly bind to and induce the activation of a transmembrane G protein-coupled receptor, protease-activated receptor 2 (PAR2). PAR2 is an important signal pathway that regulates inflammatory response. Although there are few studies on PAR2 in the field of tumors, it is conceivable that TF can affect a series of tumor function signals in cells by virtue of PAR2. In summary, TF-PAR2 induces the gene expression of key growth factors, immunoregulators, and chemokines (e.g. VEGF, CSF1/2, IL8, CXCL1, etc.), promotes neovascularization, and provides adequate nutrients, energy and a suitable microenvironment for tumor growth by MAPK/ERK phosphorylation. In addition, TF can also enhance the migration and adhesion of tumor cells by interaction with Rac 1 and β1 family-related integrin, so as to enhance the hematogenous metastatic ability of tumor cells in general (Journal of Thrombosis research, 2012, 130: S84-S87; Journal of Thrombosis and Haemostasis, 2013, 11: 285-293; International Journal of Cancer, 2014, doi: 10.1002/ijc.28959; Blood, 2012, 119: 924-932).
Meanwhile, TF-induced hypercoagulative state directly promotes survival and hematogenous metastasis of tumor cells (Blood, 2008, 111: 190-9; Cancer Res., 2015, 75 (1 Suppl): Abstract nr B19), i.e. the TF/FVIIa-initiated coagulation results in the formation of thrombin and the deposition of fibrin, which not only enables tumor cells to escape from immune attack, but also enhances the interaction between tumor cells and endothelial cells, which helps the diffusion and infiltration of tumor cells, and facilitates the occurrence of hematogenous metastasis. This is also an important reason why it is difficult to treat cancer now.
Studies have shown that TF also plays a role in thrombotic diseases. In addition to its role in the development and progression of tumor, TF or MPTF (Microparticle tissue factor)-initiated coagulation is also an important reason for triggering Venous thromboembolism (VTE), and moreover, its content in blood is directly proportional to the severity degree of VTE. Now, there are many studies showing that TF can be used as an important marker for diagnosis and assessment of the condition in VTE patients in clinic, and as a potential target for VTE treatment (Thrombosis research, 2010, 125: 511-512; Lupus., 2010, 19: 370-378; Annual review of physiology, 2011, 73: 515-525). The role of TF in arterial thrombotic diseases can not be ignored, either. A lot of clinical data indicates that TF plays an important role in the development and progression of atherosclerosis. In 2009, Steppich B A, Braun SL et al. conducted research in 174 patients with unstable Angina Pectoris (uAP) and 112 patients with Acute myocardial infarction (AMI), and the results showed that the activity of TF in plasma had a direct effect on the mortality of patients with cardiovascular disease, and TF could be used as a marker for diagnosis and prognosis of cardiovascular disease (Thrombosis research, 2012, 129: 279-284; Thromb J., 2009, 7(11): 1-9); in 2014, Jiang P, Xue D et al. conducted research to the photochemically induced thrombosis model and the FeCl3-induced thrombosis model, and showed that as compared with the intrinsic pathway of blood coagulation, the TF-initiated extrinsic pathway of blood coagulation played a more important role in the development and progression of arterial thrombotic diseases, and the experimental results further proved the TF-initiated extrinsic pathway of blood coagulation could be used as a target for the treatment of arterial thrombotic diseases (Thrombosis research, 2014, 133(4): 657-666).
TF also plays a role in inflammation and metabolic diseases. Studies have shown that the development of an inflammatory disease is accompanied by abnormal angiogenesis and coagulation. The studies conducted by Maria I Bokarewa et al. have shown that a variety of inflammatory stimuli promoted the expression of TF on the surface of endothelial cells and mononuclear cells, and their experimental results showed that overexpression of TF was also a major factor for inducing and promoting inflammation (Arthritis Res 2002, 4:190-195).
Moreover, studies have also shown that TF plays a significant regulatory role in the treatment of obesity and diabetes. For example, the studies conducted by Leylla Badeanlou et al. have shown that the blockage of TF-PAR2 signal pathway by specific antibodies targeted to TF or knocking out TF could significantly inhibit the development of diet-induced obesity and adipose tissue inflammation, and can significantly improve the therapeutic effect of insulin on diabetes (Nature medicine, 2011, 17(11): 1490-1497).
Therefore, in view of the roles and functions of TF in various relevant diseases, the development of specific therapeutic antibodies targeted to TF is extremely beneficial for the diagnosis, treatment and prevention of pathological features resulted from vascular proliferation, abnormal coagulation, and the like, which are caused by TF in various diseases such as cancer, thrombosis and inflammation.